This invention relates to a process for the preparation off a crystalline monohydrate form of a carbacephalosporin.
The .beta.-lactam antibiotic of the formula (I), ##STR2## is the potent orally active antibiotic known as loracarbef. The antibiotic is described, for example by J. Hashimoto, et al., in U.S. Pat. No. 4,335,211, issued Jun. 15, 1982.
The above compound comes in various forms, including the crystalline monohydrate form, which is disclosed in European Patent Publication 0,311,366 having a publication date of Apr. 12, 1989. The crystalline dihydrate form of the compound is disclosed in European Patent Publication 369,686 published May 23, 1990. Other known solvate forms of the compound are disclosed in Eckrich et al., U.S. Pat. No. 4,977,257. As set out in the Eckrich et al. patent, the crystalline monohydrate form of loracarbef may be derived from the loracarbef bis(DMF)solvate. The procedure for such conversion involves dissolving the loracarbef bis(DMF)solvate in water, adding hydrochloric acid followed by triethylamine. The crystalline monohydrate is then filtered from the mixture. This particular process is hampered by the inefficient removal of residual dimethylformamide (present in the intermediate loracarbef bis(DMF)solvate), and triethylamine (used to crystallize loracarbef monohydrate) from the crystals slow filtration and wash difficulties.
It has been determined that loracarbef crystalline monohydrate, which is a fine "hair-like" crystal, apparently forms a mat on the filter medium which prevents or reduces the ability to remove the occluded solvent and base. In order to obtain acceptable levels of the DMF and triethylamine it has been necessary to wash the crystals with water one or more times. Since loracarbef monohydrate is moderately soluble in water (approximately 10 mg/ml) significant yield losses result when such reslurries are needed. Added to this is the slow filterability in General of the monohydrate.
In light of the above difficulties, what is needed is a process which avoids not only the need to use acids and bases to produce the monohydrate, but also avoids the requirement for filtration, requiring only a dry down to produce the monohydrate.